For over a decade, we have conducted a series of studies exploring the physiologic and pathophysiologic implications of CRH utilizing acute and chronic antalarmin administration in rodents and non-human primates. We extended our prior work showing that antalarmin acutely suppresses key behavioral and physiological responses to stress in rhesus macaques by demonstrating similar effects when given daily to non-human primates for ninety consecutive days. On the basis of our collective work with CRH, we established a coalition of scientists from the NIMH and four other NIH Institutes to fund toxicology studies to determine the suitability of antalarmin administration to human subjects as a potential rapidly acting antidepressant and as a [unreadable] compound capable of mitigating premature systemic stigmata of major depressive illness. In studies conducted over the past 18 months, we are on the verge of receiving an IND for antalarmin from the FDA for use in human studies. This represents one of the first hypothesis-driven applications of an antidepressant agent, and is unique in its potential proposed impact on both the affective and systemic manifestations of major depressive illness.[unreadable] [unreadable] We first reported premature osteopenia and osteoporosis in premenopausal women with major depression and have now replicated this finding in a series of 92 new patients. As in our previous work, we found that, in contrast to the majority of patients with pathologic loss of bone, the loss here was greater at the hip than the spine. [unreadable] This pattern is characteristic of an inflammatory component to the bone loss, compatible with two further findings this year indicating that patients with major depression are in a sustained proinflammatory state. In the premenopausal group with bone loss noted above, we found evidence of hypersecretion of IL-6, replicating prior findings in our other studies of patients with major depression. In the light of our multiple findings implicating IL-6 hypersecretion in major depression, in collaboration with Dr. Kenner Rice, we synthesized the compound 3-O-Formyl-20R,21-epoxyresibufogenin and demonstrated that it suppresses IL-6-type cytokine actions by targeting the glycoprotein 130 subunit. This compound is a small, lipophilic molecule that is orally absorbed and that readily crosses the blood brain barrier. We are in the process of conducting studies of its role not only as an anti-inflammatory agent, but also on behavior. We and others have advanced data indicating that IL-6 secretion is stress-responsive and, acting centrally exerts behavioral effects of relevance to the symptom complex of major depression.[unreadable] [unreadable] In further studies of inflammatory mediators in patients with major, we found that medication-free patients with major depression in remission had significant elevations in the acute phase reactants serum amaloid A and C-reactive protein. We demonstrated these abnormalities on two separate occasions at least one week apart.[unreadable] [unreadable] The role of norepinephrine secretion in the syndrome of major depression has been the subject of many conflicting reports. Norepiphrine works in close concert with CRH and exerts many of the same effects on the behavioral and physiological responses to stress. Moreover, we have advanced several lines of evidence that both CRH and norepinephrine activate each others release. We found that unmedicated patients with MDD with melancholic features had significant elevations in blood pressure, pulse rate, and in around-the-clock levels of CSF NE, plasma NE, plasma epinephrine (EPI), and plasma cortisol. CSF NE, plasma NE, and plasma cortisol levels all rose progressively during the night and peaked in the morning, the time of maximal vulnerability to myocardial infarction and sudden death. Their diurnal patterns and moment-to-moment secretion were highly concurrent, so that their collective cardiotoxic effects were evident throughout the 24 hr period. For many hrs each day, the levels of plasma NE were higher than those known to double the mortality of chronic heart failure patients, providing a mechanism for the marked increase in morbidity and mortality in patients with chronic heart failure with a superimposed depression. We have replicated this finding in a larger series of patients, in whom we assessed the levels of norepinephrine and its metabolites hourly for 12 consecutive hours overnight. We are currently in the process of testing the hypothesis that this group has concomitant evidence of the hypersecretion of CRH, and that acting together, these two abnormalities contribute to other systemic manifestations of major depression that would be predicted on the basis of their dysregulation, including insulin resistance. In a study of 40 premenopausal women with major depression in remission from affective symptomatology compared to 40 BMI matched controls, we found evidence of significant relative insulin resistance, hyperinsulinemia, and dyslipidemia.